Arylhydrazones of 3,16alpha,17alpha-trihydroxy-5-pregnen-20-one and esters thereof



United States Patent .ARYLHYDRAZONES, 0F am iva-rnnrvonoxv'5-BREGNEEN-20-ONEE AND nsrnns THEREOF Raymond M. Dodson, Park Ridge,111., assignor to G. D; Searle & 00., Chicago, Ill., a corporation ofIllinois Application November 22, 19:55 Serial N0. 548,529

x 7 No Drawing.

The present invention relates to a new group of hydrazones, and isspecifically concerned with arylhydrazones of3,160,17a-trihydroxy-5-pregnen-20-one and esters thereof. The compoundsof this invention can be represented by the structural formula =N-NH-Ar|---0H wherein R and R are members of the group consisting ofhydrogenand acyl radicals derived from lower alkanoic acids, and Ar isan aromatic hydrocarbon radical containing fewer than 10 carbon atoms.The group Ar can consequently represent such monocyclic, aromaticradicals as phenyl, tolyl, ethylphenyl, propylphenyl, xylyl, andtrimethylphenyl. -"The terms R and R in the foregoing structuralrepresentation include such acyl radicals as formyl, acetyl, propionyl,butyryl, valeryl, hexanoyl, heptanoyl, octanoy-l, and branchedchainisomers thereof. These groups are acyl'radicals' with phenylhydrazine inglacial acetic acid results in the addition of acetic acid to theepoxide ring and the formation of the phenylhydrazone ofl6oa-acetoxy-3B, 17a-dihydroxy-5-pregnen-20-one. This compound can beconverted to 313,16a,lla-trihydroxy-S-pregnen-ZO-one and to other estersthereof by procedures described hereinafter. Reaction products in whichR,' R and Ar represent various other groups can be conveniently obtainedby a proper selection of starting materials. Th us, re-

2,894,961 Patented July 14, 1959 action of 3.}8acetoxy-16u,17a-epoxy-5-pregnen-20-one with p-tolylhydrazine inpropionic acid affords the ptolylhydrazone of 36acetoxy-l6oc-propionoxy-17u-hydroxy-S-pregnen-ZO-one. v

- The compounds of the present invention are useful as chemicalintermediates. In a copending application of'Frank B. Colton, Serial No.461,925, filed October 12, 1954, representative compounds ofthepresentinvention and their conversion to 16a,17a-dihydroxypregnen-ZO-onederivatives have been described. In addition, the arylhydrazones of thisinvention have valuable pharmacological properties and are potenthypotensive agents.

This invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesareigiven in degrees centigrade C.) and quantities of materials in partsI by weight.

Example 1.

j Under a nit'rogenatmosphere a mixture of 725 parts of- 16oc,176c-epoxy-3,fl-hydroxy-S-pregnen-ZO-one, 796 ofphenylhydrazine and 7600'parts ofglacial ace-' tic acid-is permitted to stand at about 25 C. for-13 hours. The resulting precipitateis collected on a-fil ter,washed'with 67% acetic acid and purified by recrystallization fromaqueous methanol. An additional quantity of product is obtained byconcentration or dilution ofthe acetic acid'liquor. The phenylhydrazoneof 16oz-acetoxy-3B, 17o -dihydroxy-S-pregnen 20-one thusobtaine'd melts'with decomposition to an orange melt' at about ZZZ-223 C. compound hasthe structural formula Example '2 1 A mixture' of 50 parts of16a,17u-epoXy-3B- hydroxy- 5-pregnen-20-one, 62 parts ofp-tolylhydrazine and 500 parts .of propionic acid is allowed to stand ina nitrogen C. for 24 hours. The resulting atmosphere at about 25 filterand washed. An addiprecipitate is collected on a tional quantity ofproduct is obtained by dilution of the.

propionic acid liquor. This compound is the p-tolylhyd raz one of16a-propionoxy-3 8,l7u-dihydroxy-5-pregnen- 20-one having the structuralformula Example 3 A solution of 200 parts of the phenylhydrazone of 16uacetoxy-3/8,17a dihydroxy-S pregnen-ZO-one, 1600 .parts of methanol and200 parts of sodium methoxide is heated at the boiling point in an openreaction Vessel for 30 minutes. The mixture is then diluted with wateruntil it becomes cloudy, and allowed to cool. The precipitated productis collected on a filter and Washed with water. Recrystallization from amixture of acetone and cyclohexane affords white crystals of thephenylhydrazone of 3 9,160,l7a-trihydroxy-5-pregnen-20one, melting withdecomposition to a yellow melt at about A mixture of 1 part of thephenylhydrazone of l6oc- I acetoxy-3p,17a-dihydroxy-S-pregnen-ZO-one, 50parts of pyridine and 55 parts of acetic anhydride is maintained atabout 25 C. for 15 hours and then diluted withice water. Theprecipitated product is collected on a .filter and purified byrecrystallization from aqueous methanol. The phenylhydrazone of3B,1Got-diflCC'tOXY-l70c-hYdITOXY- S-pregnen-ZO-one thus obtained meltswith decomposition at about 216-217 C. The ultraviolet absorptionspectrum shows a maximum at 273.5 millimicrons with a molecularextinction coeificient of 23,500. This compound has the structuralformula Example 5 A solution of 2.7 parts of the phenylhydrazone of3,8,16a,17u-trihydrQXy-S-pregnen-20-one, 100 parts of pyridine and 105parts of acetic anhydride is allowed to stand at about 25 C. for '15hours. It is diluted with ice water until precipitation of the reactionproduct is complete. This product is collected on a filter, washed withwater and purified by repeated crystallizations from aqueous methanol.In this manner there is obtained the phenylhydrazone of3,8,16a-diacetoxy-17whydroxy-5- pregnen-ZO-one, identical withthe-product of Example 4.

Example 6 By the procedure of Example'l, with the substitution of 820parts of 16a,17a-epoxy-3B-acetoxy-5-pregnen-20- one for the16a,l7a-epoxy-BB hydroxy-S-pregnen-ZO-one, there is obtained thephenylhydraz'one of 3fi,l6a-diacetoxy-l7a-hydroxy-5@pregnen-20-one,identical with the product of Example 4.

Example 7 A mixture of 10 parts of 16a,17a-epoxy-3B-hydroxy-5-pregnen-ZO-one, parts of 2,4,5-trimethylphenylhydrazinc and 115 parts ofbutyric acid is allowedto stand in CHaCOO d a nitrogen atmosphere atabout 25 C. for 48 hours. Water is then added and, when separation ofthe insoluble product is complete, it is collected on a filter andwashed with dilute acetic acid and then with water. This product is the2,4,5-trimethylphenylhydrazone of 16a-butyroxy- 35, 1704-dihydroxy-S-pregnen-ZO-one.

Example 8 A solution of 3.5 parts of the 2,4,5-trimethylphenylhydrazoneof 16a-butyroxy-3fl,17a-dihydroxy-5-pregnen- ZO-one, parts of pyridineand 50 parts of propionic anhydride is allowed to stand at about 25 C.for 2 hours. It is diluted with ice water and, when separation of theproduct is complete, it is collected on a filter and washed with water.This product is the 2,4,5-trimethylphenylhydrazone of16a-butyroxy-17a-hydroxy-3fi-propionoxy- 5-pregnen-20-one of thestructural formula CHaCHzCOO What is claimed is:

1. A compound of the structural formula T on wherein the .acyl radicalis derived from a lower alkanoic hydrogen and acyl radicals derived fromlower :alkanoic acids, and Ar is an aromatic hydrocarbon radicalcontaining fewer than 10 carbon atoms.

2. A compound of .the structural formula wherein the acyl radical isderived from alower alkanoic acid, and Ar is an aromatic hydrocarbonradical containing fewer than 10 carbon atoms.

3. A compound of the structural formula wherein the acyl radical isderived from a lower alkanoic ac1d.

4. Phenylhydrazone of 16m-acetoxy-3fl,17a-dihyd1'oxy- 5-pregnen-20-one.

5. Phenylhydrazone of 3B,16u-diacetoxy-17u-hydroxy- 5-pregnen-20-one.

6. Phenylhydrazone nen-20-one.

of 3B,16a,17a-trihydroxy-5-preg- References Cited in the file of thispatent UNITED STATES PATENTS

1. A COMPOUND OF THE STRUCTURAL FORMULA